MXPA05005333A

MXPA05005333A - Perindopril.

Info

Publication number: MXPA05005333A
Application number: MXPA05005333A
Authority: MX
Inventors: Narayanrao Kankan Rajendra
Original assignee: Cipla Ltd
Priority date: 2002-11-18
Filing date: 2003-11-18
Publication date: 2005-08-16
Also published as: PT1565485E; RU2005119162A; AU2003283588A1; IS7893A; ZA200503979B; EP1565485A1; RU2339645C2; ES2333153T3; JP2013006839A; EP1565485B1; TNSN05140A1; IL168660A; DE60311516T2; EP1688427A1; JP5110770B2; ATE445632T1; CA2506587A1; CN100371345C; GB0226885D0; GEP20105036B

Abstract

A pharmaceutically acceptable salt of perindopril of formula (I) is made from a protected precursor compound of formula (II) wherein R represents a carboxyl protecting group, which process comprises subjecting a compound of formula (II) to deprotection of the carboxylic group COOR attached to the heterocyclic ring so as to yield the corresponding free acid, which deprotection is carried out in the presence of a base which forms a pharmaceutically acceptable salt with said free acid formed by said deprotection.

Description

PERINDOPRIL FIELD OF THE INVENTION This invention relates to a process for preparing a pharmaceutically acceptable salt of perindopril, and a new polymorphic form thereof. BACKGROUND OF THE INVENTION Perindopril is the international non-proprietary name of the acid. { 2S, 3aS, 7aS) -l-. { 2- [1- (ethoxycarbonyl) - (S) -butylamino] - (S) -propionyl} -octahydroindol-2-carboxylic acid. Perindopril is known to have therapeutic application as an inhibitor of the enzyme that converts angiotensin (ECA). ACE is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to angiotensin II, as well as the degradation of bradykinin. Angiotensin II is a vasoconstrictor which also stimulates the secretion of aldosterone by the adrenal cortex. The inhibition of ECA has therefore been shown to have therapeutic utility in patients suffering from disease states such as hypertension and congestive heart failure. In addition, it has been discovered that ACE inhibitors are useful for treating cognitive disorders. Perindopril has the following structural formula (I) REF. : 16 175 perindopril is described in U.S. Patent No. 4508729. The preparative processes described in this U.S. Patent are carried out in an alcoholic medium, and in the presence of a neutral dehydrating agent and an organic or inorganic cyanoborohydride. The deprotection processes can be carried out where they are necessary, for example, with reference to hydrolysis and / or hydrogenolysis. U.S. Patent No. 4914214, describes a process for the preparation of perindopril and its t-butylamine salt. The process comprises condensation of a protected ester of (2S, 3aS, 7aS) -2-carboxyperhydroindol with the diastereomer (S, S) of N- [(S) -l-carbethoxybutyl] - (S) -alanine, followed by deprotection using charcoal containing 5% palladium and water. The tertiary butylamine is then added to provide the t-butylamine salt of perindopril. PCT patent application WO 01/87835 discloses a new crystalline form, ie crystalline form or, of the t-butylamine salt of perindopril, processes for preparing it and pharmaceutical formulations containing them. PCT patent application WO 01/87836 discloses a new crystalline form, ie the crystalline form, of the t-butylamine salt of perindopril, processes for preparing it and pharmaceutical formulations containing the same. PCT patent application WO 01/87835 discloses a new crystalline form, ie, the crystalline form, of the t-butylamine salt of perindopril, processes for preparing it and pharmaceutical formulations containing the same. PCT patent application WO 01/58868, describes a process for preparing perindopril or pharmaceutically acceptable salts thereof, wherein the processes provide perindopril, or a salt thereof, with improved purity. More particularly, the level of known impurities associated with perindopril or a salt thereof, prepared in accordance with PCT patent application WO 01/58868, is described as being less than 0.2 6 0.1% by weight. The steps of the intermediate process are carried out in the presence of 1-hydroxybenzotriazole, dicyclohexylcarbodiimide and optionally triethylamine, and at a temperature in the range of 20 to 77 ° C, followed by deprotection and where salt conversion is required. The prior art processes for the preparation of perindopril or pharmaceutically acceptable salts thereof, have been generally assisted by being time consuming and have often resulted in undesirable associated impurities, such as diketopiperazine analogs. There is, therefore, a need for an improved process for preparing perindopril, or pharmaceutically acceptable salts thereof, which alleviate the aforementioned problems. DETAILED DESCRIPTION OF THE INVENTION It has now been developed, a process for preparing a pharmaceutically acceptable salt of perindopril, which is advantageous in terms of a faster reaction time, compared to known processes for the preparation of a pharmaceutically acceptable salt of perindopril, and also obviating the production of undesirable impurities for achieve a highly pure product. In accordance with one aspect of the present invention, there is provided a process for preparing a pharmaceutically acceptable salt of perindopril of formula (I), from a protected precursor compound of formula (II). wherein R represents a carboxyl protecting group, wherein the process comprises subjecting a compound of formula (II) to deprotection of the carboxylic group COOR attached to the heterocyclic ring, in order to provide the corresponding free acid, in which deprotection is carried performed in the presence of a base which forms a pharmaceutically acceptable salt with said free acid formed by said deprotection. Typically, R can represent any suitable carboxyl protecting group that can be selectively removed by a process according to the present invention. Preferably, R can represent optionally substituted aralkyl, especially optionally substituted benzyl. R may, therefore, typically represent unsubstituted benzyl; alternatively substituted benzyl can be employed, such as -halo substituted or 4-substituted alkoxy-4-benzyl, especially 4-C1 of benzyl or 4-methoxybenzyl. Suitably, deprotection as employed in a process according to the present invention, may comprise hydrogenolysis in the presence of a noble metal catalyst, preferably palladium in carbon. The process of the present invention is advantageous, achieving a highly pure product. A pharmaceutically acceptable salt of perindopril prepared by a process according to the present invention, is preferably more than about 99% pure p / p, and more preferably more than about 99.5% pure p / p. The purity of a pharmaceutically acceptable salt of perindopril prepared by a process according to the present invention can be further enhanced by an optional crystallization step in a suitable solvent, such as ethyl acetate, isopropanol or the like, to obtain a pharmaceutically salt acceptable perindopril, which is preferably about 99.8% pure w / w. Preferably, the base employed in the process of the present invention is selected to form a pharmaceutically acceptable salt with the free acid formed by the deprotection as indicated above, thereby, it is possible to obtain a pharmaceutically acceptable salt of perindopril directly from such lifting reaction. In a particularly preferred embodiment according to the present invention, the base comprises t-butylamine and as such, a preferred process according to the present invention, can provide a highly pure t-butylamine salt of perindopril directly from the process of reaction. In accordance with the above preferred embodiment of the present invention, there is provided a process for preparing t-butylamine from perindopril (which is well known to those skilled in the art for being perindopril erbumin), from a protected precursor compound of formula (II) substantially as described hereinbefore (preferably a protected benzyl precursor compound of formula (II), wherein R represents benzyl), wherein the process comprises subjecting a compound of formula (II) to deprotection (preferably hydrogenolysis in the presence of a noble metal catalyst such as palladium in carbon) of the COOR carboxylic group attached, to the heterocyclic ring to provide the corresponding free acid, in which, the deprotection is carried out in the presence of t-butylamine for form the t-butylamine salt of perindopril. Suitably, a precursor compound of formula (II) is initially dissolved in an alkanol solvent, such as isopropanol or the like, followed by addition of the base thereof. This is further followed by the deprotection of the carboxylic group COOR, suitably by the addition of palladium in carbon and hydrogenation for several hours. The alkanol solvent is suitably concentrated under vacuum and replaced by a water-miscible solvent, such as ethyl acetate or the like. The resulting solids can then be cooled and filtered to provide a pharmaceutically acceptable salt of perindopril. The process according to the present invention, substantially as described hereinbefore, may further comprise hydrating a pharmaceutically acceptable salt of perindopril obtained by the process to provide a pharmaceutically acceptable salt of perindopril hydrate of formula (la). where n is an integer from 1 to 5, or a reciprocal of whole numbers 2 to 5. Hydration can be by adding water or by air drying. Preferably n is 1, wherein a pharmaceutically acceptable salt of perindopril monohydrate is formed by a process in accordance with the present invention. The present invention also provides a process for preparing a monohydrate of a pharmaceutically acceptable salt of perindopril, wherein the process comprises hydrating a pharmaceutically acceptable salt of perindopril to provide said monohydrate. The hydration can be by means of the addition of water or by drying in air, and preferably, t-butylamine of perindopril is hydrated to provide the t-butylamine monohydrate of perindopril. The present invention further provides a pharmaceutically acceptable salt of perindopril optionally in hydrated form, prepared by a process substantially as described hereinabove. In particular, a pharmaceutically acceptable salt of perindopril hydrate of formula (la) is provided. wherein n is an integer from 1 to 5, or a reciprocal of whole numbers 2 to 5. Preferably, n is 1. A preferred pharmaceutically acceptable salt of perindopril hydrate of formula (la) is the t-butylamine salt. In a particularly preferred embodiment, the present invention provides t-butylamine (or erbumine) monohydrate of perindopril. The present invention also provides t-butylamine monohydrate of perindopril having an X-ray diffractogram, or substantially the same x-ray diffractogram, as set forth in Figure 1. More particularly, the t-butylamine monohydrate of perindopril In accordance with the present invention, it can be characterized by having an X-ray powder diffraction pattern with characteristic peaks (2T): 9.5504, 14.8600, 15.7486, 16.5400, 20.0400, 21.0499, 22.0600, 24.1744, 26.3300 and 27.1600. Additional characterizing data for perindopril t-butylamine monohydrate according to the present invention, obtained by X-ray diffraction, are shown in the following Table 1. Table 1 Peak No. 2T d ra FWHM Integrated Intensity 1 (degrees) (A) (degrees) (Counts) (Counts) 1 8.6400 10.22611 10 0.57600 151 6899 2 9.5504 9.25324 73 0.50470 1090 28204 3 10.5940 8.34394 5 0.97200 79 4071 4 13.6000 6.50569 6 0.42860 91 2112 5 14.1400 6.25844 14 0.47120 215 5210 6 14.8600 5.95678 22 0.59000 332 10293 7 15.7486 5.62262 75 0.14270 1111 49244 8 16.5400 5.35533 30 0.72500 450 15749 9 17.5400 5.05220 16 0.67120 231 9128 10 18.6100 4.76406 17 0.56000 249 7981 11 20.0400 4.42722 31 0.51660 458 13471 12 23,1600 3.83738 17 0.71720 253 12014 15 24.1744 3.67860 47 0.50030 705 17912 16 24.8000 3.58721 5 0.26000 73 1463 17 26.3300 3.38213 31 0.94000 468 19402 18 27.1600 3.28062 20 0.68500 292 9230 19 28.4444 3.13534 15 0.96890 223 11023 20 30.8000 2.90071 7 0.59340 99 3196 21 31.8000 2.81173 9 0.65600 130 4356 22 32.5600 2.74782 11 0.61340 163 4411 23 33.2400 2.69314 6 0.75000 95 311 6 24 34.1800 2.62120 4 0.64000 61 2155 25 35.4728 2.52857 7 0.85430 104 4353 26 36.8838 2.43502 6 0.61900 93 2985 27 38.7340 2.32285 4 0.50800 55 1432 Perindopril provided by the present invention has therapeutic utility as an ACE inhibitor. In addition, the present invention further provides a method for inhibiting ACE in a patient in need thereof, comprising administering to said patient, an effective ECA inhibitory amount of perindopril (preferably, t-butylamine monohydrate of perindopril), provided in accordance with the present invention. The present invention also provides the use of perindopril provided in accordance with the present invention (preferably, t-butylamine monohydrate of perindopril) in the manufacture of a medicament for inhibiting ACE.

A patient may be in need of treatment to inhibit ACE, for example, when the patient is suffering from hypertension, chronic congestive heart failure, or the like. The inhibition of ACE reduces levels of angiotensin II. and in this way, it inhibits the vasopressor, hypertensive and hyperaldosteronemic effects caused thereby. ACE inhibition may also potentiate endogenous bradykinin levels. An inhibitory amount of the effective ECA of perindopril provided in accordance with the present invention is such an amount which is effective in inhibiting ACE in a patient in need thereof, which results, for example, in a hypotensive effect. By effecting treatment of a patient, the perindopril provided in accordance with the present invention can be administered in any form or manner which makes the compound bioavailable in effective amounts, including oral and parenteral routes. For example, perindopril provided according to the present invention can be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally and the like. Oral administration is generally preferred. One skilled in the art to prepare formulations can easily select the appropriate form and mode of administration depending on the state of the disease to be treated and the stage of the disease. The perindopril provided in accordance with the present invention can be administered in the form of pharmaceutical compositions or medicaments which are prepared by combining the perindopril according to the present invention with pharmaceutically acceptable carriers, diluents or excipients thereof, the proportion and nature of which are determined by the chosen route of administration and standard pharmaceutical practice. In another embodiment, the present invention provides pharmaceutical compositions comprising an inhibitory amount of the effective ECA of perindopril provided in accordance with the present invention (preferably, t-butylamine monohydrate of perindopril), together with one or more carriers, diluents or excipients thereof pharmaceutically acceptable. By "pharmaceutically acceptable", it means that the carrier, diluent or excipient, must be compatible with perindopril provided in accordance with the present invention and not be harmful to a container thereof. The pharmaceutical compositions or medicaments are prepared in a manner well known in the pharmaceutical art. The carrier, diluent or excipient may be a solid, semi-solid, or liquid material, which may serve as a vehicle or medium for the active ingredient. Suitable carriers, diluents or excipients are well known in the art. Pharmaceutical compositions according to the present invention, can be adapted for oral or parenteral use and can be administered to the patient in the form of tablets, capsules, suppositories, solutions, suspensions or the like. The pharmaceutical compositions can be administered orally, for example, with an inert diluent or with an edible carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For purposes of oral therapeutic administration, a monohydrate according to the present invention can be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups and the like. Tablets, pills, capsules and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients, such as starch or lactose; disintegrating agents such as alginic acid, corn starch and the like; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; and sweetening agents, such as sucrose or saccharin. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other unit dosage forms may contain various other materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills can be coated with sugar, shellac or other enteric coating agents. A syrup may contain, in addition to the active ingredient, sucrose as a sweetening agent and certain preservatives. Materials used in the preparation of these various compositions must be pharmaceutically pure and non-toxic in the amounts used. For purposes of parenteral administration, the perindopril provided in accordance with the present invention can be incorporated into a solution or suspension. The solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diamine tetraacetic acid; and buffers such as acetates, citrates or phosphates. The parenteral preparation can be encapsulated in ampules, disposable syringes or multiple dose vials made of glass or plastic. The present invention will now be further illustrated by the following Figure and Examples, which do not limit the scope of the invention in any way. Figure 1: X-ray diffraction pattern of perindopril erbumine monohydrate according to the present invention. The sample was analyzed using a Shimadzu-6000 X-ray diffractometer. The source used was Ka monochromatic radiation of Cu having a wavelength of 1.5406 A. The diverging strip used was I. The receiving strip was 0.30 mm. The scintillation counter was used as the detector, with the range being from 3o to 4o (2?) With a scanning speed of 2o per minute Example 1 The benzyl ester of (2S, 3aS, 7aS) -l- acid { 2- [1- (ethoxycarbonyl) - (S) -butylamino] - (S) -propionyl.}. -octahydroindol-2-carboxylic acid, ie, benzyl perindopril (10 gms), was dissolved in isopropanol (100 ml. To the clear solution, t-butylamine (2.5 gms) and palladium on charcoal at 10% w / w (2 gms) were added.The tion mixture was hydrogenated at a pressure of 1 kg / cm 2 for 2 hours.

The reaction mass was filtered to remove the catalyst. The solvent was concentrated under vacuum and isopropanol was replaced by the simultaneous addition of ethyl acetate. The obtained solids were cooled to OEC and filtered to obtain perindopril erbumin (7.8 gms). Example 2 Perindopril erbumine (10 gms) was suspended in acetone (80 ml). To this was added water (0.4 ml) and the contents were heated to dissolve the solids and cooled to room temperature. The resulting suspension was filtered to obtain erindole monohydrate of perindopril (9.4 gms). Example 3 Perindopril erbumine (20 gms) was suspended in ethyl acetate (300 ml). To this water (1.5 ml) was added and the contents were heated to dissolve the solids and cooled to 10E.C. The resulting suspension was filtered to obtain erindole monohydrate of perindopril (17 gms). Example 4 Perindopril erbumine (5 gms) was suspended in acetonitrile (75 ml). To this was added water (0.4 ml) and the contents were heated to dissolve the solids and cooled to OEC. The resulting suspension was filtered to obtain erindole monohydrate of perindopril (2.9 gms). Example 5 Perindopril erbumine (20 gms) was suspended in ethyl acetate (300 ml). The contents were heated to dissolve the solids and cooled to 10EC. The resulting suspension was filtered and dried in air having relative humidity of at least 75% to give erindoin monohydrate perindopril (17 gms). Example 6 Preparation of erindoin monohydrate from perindopril Pure materials: 1. Erindoin perindopril anhydrous = 10 gm. 2. Isopropyl alcohol = 70 ml. 3. Water = 2 mi. 4. Ethyl acetate = 85 ml.

Procedure: > 1. Load 10 gm of perindopril erbumine (anhydrous) in a ball flask. Add 70 ml of isopropyl alcohol. Stir for 1/2 hour (about 95% dissolved product). 2. Add 2 ml of water. Stir for 15 minutes (clear solution obtained). 3. Shake the reaction mass at 38-40 ° C for 2 hours. 4. Distill isopropyl alcohol completely under vacuum (below 600 mm) below 40 ° C (Gel type material observed). 5. Charge 30 ml of ethyl acetate. Shake for 15 min. below 40 ° C (clear solution observed). Distill under vacuum below 40 ° C (semi-solid observed). 6. Charge 40 ml of ethyl acetate at 36-38 ° C. Stir for 15 minutes (free solid observed). 7. Stir 1 hr at room temperature (25-30 ° C). (Free crystalline solid observed). 8. Cool to 10 ° C. Shake for 2 hours. 9. Filter the solid and wash with 15 ml of ethyl acetate. Dry by suction for 2 hours. 10. Dry under vacuum below 40 ° C for 12 hours.

Water content P.F. = 145-150 ° C.

Example 7 The following tablets were prepared: (a) Formulation I: Procedure: Sift the previous ingredients through respective sieves. Mix the ingredients in a suitable mixer. Compress the tablets in the right work tools. (b) Formulation II: Procedure: 1) Dissolve Erindoin Monohydrate of perindopril in ethanol. 2) Granulate the previous ingredients, except hydrogenated castor oil with the previous solution. Dry the granules and classify. 3) Lubricate with hydrogenated castor oil in a suitable mixer. Compress the granules in the right tools. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property; 1. Process for preparing a pharmaceutically acceptable salt of perindopril of formula (I) from a protected precursor compound of formula (II). (?) Q) characterized in that R represents a carboxyl protecting group, in which, the process comprises subjecting a compound of formula (II) to deprotection of the carboxylic group COOR attached to the heterocyclic ring, so as to provide the corresponding free acid, in the which deprotection is carried out in the presence of a base which forms a pharmaceutically acceptable salt with said free acid formed by said deprotection. Process according to claim 1, characterized in that R represents optionally substituted aralkyl. Process according to claim 2, characterized in that R represents unsubstituted benzyl. 4. Process according to claim 2, characterized in that R represents 4-halo substituted, or 4-C 1 -C 4 substituted alkoxy benzyl. Process according to claim 4, characterized in that R represents 4-Cl of benzyl, or 4-methoxy-benzyl. 6. The process according to claim 1, characterized in that the deprotection comprises hydrogenolysis in the presence of a noble metal catalyst. Process according to claim 6, characterized in that the noble metal catalyst comprises palladium in carbon. 8. Process according to any of claims 1 to 7, characterized in that said base comprises t-butylamine. 9. Process for preparing t-butylamine from perindopril from a protected precursor compound of formula (II) (II) characterized in that R represents a carboxyl protecting group, in which the process comprises subjecting a compound of formula (II) to deprotection of the carboxylic group COOR attached to the heterocyclic ring to provide the corresponding free acid, in which, the deprotection is carried out in the presence of t-butylamine to form the t-butylamine salt of perindopril. 10. Process according to claim 9, characterized in that R represents unsubstituted benzyl. 11. Process according to claim 9 or 10, characterized in that the deprotection comprises hydrogenolysis in the presence of palladium in carbon. 12. Process according to any of claims 1 to 11, characterized in that it further comprises hydrating a pharmaceutically acceptable salt of perindopril obtained by said process to provide a pharmaceutically acceptable salt of perindopril hydrate of formula (Ia) wherein n is an integer from 1 to 5, or a reciprocal of whole numbers from 2 to 5. Process according to claim 12, characterized in that n is 1. Process for preparing a monohydrate of a pharmaceutically salt acceptable perindopril, characterized in that the process comprises hydrating a pharmaceutically acceptable salt of perindopril to provide said monohydrate. 15. Process according to any of claims 12 to 14, characterized in that the t-butylamine of perindopril is hydrated to provide t-butylamine monohydrate of perindopril. 16. Pharmaceutically acceptable salt of perindopril optionally in hydrated form, characterized in that it is prepared by a process according to any of claims 1 to 15. 17. Pharmaceutically acceptable salt of perindopril hydrate of formula (Ia) characterized by the fact that n is an integer from 1 to 5, or a reciprocal of whole numbers from 2 to 5. 18. Pharmaceutically acceptable salt according to claim 17, characterized in that n is 1. 19. Pharmaceutically acceptable salt according to claim 17 or 18, characterized in that it is the t-butylamine salt. 20. Perindopril t-butylamine monohydrate.,twenty-one. Perindopril t-butylamine monohydrate, characterized in that it has an X-ray diffractogram, or substantially the same X-ray diffractogram as set forth in Figure 1. 22. Perindopril t-butylamine monohydrate, characterized by having a standard Diffraction powder X-ray with characteristic peaks (2T): 9.5504, 14.8600, 15.7486, 16.5400, 20.0400, 21.0499, 22.0600, 24.1744, 26.3300 and 27.1600. 23. Pharmaceutical composition characterized in that it comprises an inhibitory amount of the effective ECA of a pharmaceutically acceptable salt of perindopril according to any of claims 16 to 22, together with one or more pharmaceutically acceptable carriers, diluents or excipients thereof. 24. Use of a pharmaceutically acceptable salt of perindopril according to any of claims 16 to 22, in the manufacture of a medicament for inhibiting ACE. 25. Method for inhibiting ACE in a patient in need thereof, characterized in that it comprises administering to said patient, an effective ECA inhibitory amount of a pharmaceutically acceptable salt of perindopril according to any of claims 16 to 22.